The invention relates to the preparation of imidazole derivatives and more particularly to the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers.
Imidazole derivatives, in particular, 1-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole, commonly referred to as tioconazole, are known for their antifungal therapeutic properties. U.S. Pat. No. 4,062,966 discloses a process for the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers which employs arylation of an appropriate 1-aryl-2-(1-imidazolyl)alkanol or alkane thiol having the formula 
wherein R1 to R4 are each H or C1-6 alkyl, Ar is phenyl, or substituted phenyl wherein said substitutents are halogen, C1-6 alkyl, C1-6 alkoxy, thienyl, or halothienyl, and, Z is oxygen or sulfur. In accordance with US ""966, the reaction comprises converting the alcohol or thiol in a suitable solvent to its alkali metal derivative by treatment with a strong base, such as an alkali metal amide or hydride, and reacting with the appropriate aralkyl halide of the formula 
where n is 1 or 2, Y is an aromatic heterocyclic group or substituted heterocyclic group, wherein substitutents are halogen, C1-6 alkyl, or C1-6 alkoxy atoms, thienyl or halothienyl group, and X is a halogen, preferably chlorine. Tetrahydrofuran (THF) is the preferred solvent taught in US ""966. Reaction temperatures may range from about 0xc2x0 C. to reflux temperature of the solvent and reaction times range from about 1 hour to about 24 hours. The product is isolated with water, extracted with ether, and may be purified as the free base or converted to a salt, e.g. the hydrochloride, and purified by recrystallization.
A disadvantage of the process disclosed in US ""966 is that THF is a peroxide generator which presents the potential for an explosion. From a commercial viewpoint, peroxide generators are not preferred due to the dangers associated therewith.
GB 1 522 848 discloses a process for the preparation of imidazoles useful as antifungal agents involving a labor intensive, multi-sequence reaction of an imidazole ether with a reactive ester. Like US ""966, THF is employed presenting similar concerns in the synthesis of the desired imidazole product.
According to the Pharmaceutical Manufacturing Encyclopedia, tioconazole is prepared by dissolving 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol in THF and sodium hydride and heating to about 70xc2x0 C. The resulting mixture is then contacted with 2-chloro-3-chloromethylthiophene and heated to reflux (about 67xc2x0 C.). The resulting product is filtered, saturated with hydrogen chloride, triturated and recrystallized to obtain the purified tioconazole hydrochloride product having a melting point of about 170xc2x0 C. This salt must then be freebased to form the product used in pharmaceutical formulations. This route, like those discussed above, also presents the dangers of a potential explosion.
There is thus a continuing need for a commercially viable, synthetic route for the production of imidazoles, in particular tioconazole.
The present invention relates broadly to a novel process for the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers comprising (a) alpha bromination of an aromatic or a heterocyclic compound, or more particularly a thiophene derivative under suitable reaction conditions; and, (b) coupling under suitable reaction conditions the product of step (a) with an imidazole, preferably an imidazolyl ethanol derivative.
For exemplary purposes, the present invention is described in particular detail with respect to the preparation of tioconazole. It is to be understood that the process is applicable to other aromatic or heterocyclic compounds, e.g. econazole or miconazole.
Relative to the preparation of tioconazole, it is preferred that the product of step (b) be converted to a bisulfate salt for ease of isolation and purification of the final product. Reaction conditions for step (a) include free radical alpha bromination, preferably employing n-bromosuccinimide (NBS) in a refluxing aliphatic solvent such as cyclohexane. Reaction conditions for step (b) include a temperature range of about 15xc2x0 C. to about 30xc2x0 C., use of an alcohol or short chain (e.g., C5-10) aliphatic hydrocarbon as solvent, and employing a reaction time of from about 1 to about 24 hours.
The present invention relates broadly to a process for the preparation of 1-aryl-2-(1-imidazolyl) alkyl ethers and thioethers comprising
(a) alpha brominating an aromatic or heterocyclic compound, preferably a thiophene derivative under suitable reaction conditions; and,
(b) coupling the product of step (a) with an imidazole, preferably an imidazolyl ethanol derivative under suitable reaction conditions. Purification of the product of step (b) is preferably accomplished as the bisulfate salt.
More specifically, the present invention relates to a process for the preparation of tioconazole comprising (a) alpha bromination of 2-chloro-3-methylthiophene, using NBS in the presence of a peroxide and aliphatic solvent under suitable reaction conditions; and, (b) contacting the product solution of step (a) with 1-(2,4-dichlorphenyl)-2-(1-imidazolyl)ethanol under suitable reaction conditions.
The reaction will be described below relative to each reaction step.
Alpha Bromination:
One embodiment of the present invention involves, as step (a), alpha bromination with a brominating agent in the presence of an aliphatic solvent and a free radical initiator. Any suitable brominating agent may be employed. Suitable brominating agents include but are not limited to NBS, molecular bromine, 1,3-dibromo-5,5-dimethyl hydantoin, n-bromoacetamide. N-bromosuccinimide is the preferred brominating agent.
The process may be employed to brominate the alkyl side chain of alkyl-substituted heterocyclic or aromatic compounds. The alkyl side chain can have from 1 to about 4 carbon atoms and is preferably a saturated hydrocarbyl radical. Typical of such alkyl side chains include methyl, ethyl, propyl and butyl radicals. Preferably, the alkyl radical is a methyl radical.
Typical of the aryl or heterocyclic compounds with which the brominated intermediate (produced by the process of step (a)) can be employed include toluene, thiophene, furan, pyridine, 2-methylpyridine, lutidine, methylquinoline, dimethylfuran and similar heterocyclic compounds. Thiophene compounds are of particular interest. Most preferred are 2- and 3-methyl thiophene and most particularly preferred is 3-methyl thiophene.
The molar ratio of brominating agent to aryl or heterocyclic is preferably 1:1. However, an excess of starting heterocyclic material above stoichiometric can be employed.
The alpha bromination is preferably carried out in a solvent that facilitates the alpha bromination. Prior art studies have shown that certain brominators take place with more facility in one solvent versus another solvent. It has been found that aliphatic solvents, such as hexane, and in particular cycloaliphatic solvents such as cyclohexane show good selectivity. It has also been found that satisfactory selectivity and yield can be obtained by carrying out the process of step (a) with an initial concentration of heterocyclic of about 5 to about 20 percent (%) by weight (wt) in the solvent.
The time of the reaction is only that necessary to complete the reaction and the reaction can generally be carried out at elevated temperature (e.g., refluxing cyclohexane) under atmospheric conditions. Generally, reaction times for step (a) comprise about 1 hour to about 12 hours. More generally the reaction is performed in about 4 hours.
In general, suitable organic peroxides may be employed as free radical initiators. Suitable initiators include but are not limited to peracetic acid, perbenzoic acid, perbutyric acid, toluenesulfonic acid, benzoyl peroxide, azobisisobutyronitrile, and the like, with benzoyl peroxide being the preferred initiator. Generally a catalytic amount of peroxide is employed to achieve complete conversion. The weight ratio of peroxide to thiophene is about 0.01 to about 0.30, in particular about 0.01 to about 0.10, and most preferred about 0.02 to about 0.08.
In one embodiment of the present invention, 2-chloro-3-methylthiophene is brominated with NBS and benzoyl peroxide as a radical initiator. We have discovered good selectivity to the alpha brominated material (results in about 75% yield ) with this reaction step. Reaction proceeds through this brominated site.
A significant point of this particular reaction is that this is a Wohl-Zeigler reaction which is generally run in carbon tetrachloride solvent. With carbon tetrachloride one must usually isolate the intermediate since the solvent can then react further with the product of the coupling step. We have discovered that cyclohexane may be employed as a solvent with this Wohl-Zeigler reaction. Once the desired brominated product is formed, one may easily filter off the solid succinimide byproduct formed. It is recommended as the easiest, and most safe route, to not isolate the brominated thiophene product of step (a), but take the crude solution and proceed to the subsequent coupling reaction.
Coupling:
The solution product of step (a) is coupled with an imidazolyl derivative with a base and alcohol as solvent. A preferred imidazolyl derivative is 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol, but others may be employed. The cyclohexane solution product of step (a) is poured into an imidazolyl, hydroxide, alcohol reaction mixture. At this point, a mixed solvent system of cyclohexane and alcohol is present. The coupling reaction is conducted at room temperature, generally run overnight, and results in the desired tioconazole product with sodium bromide as a byproduct. Yields of about 40% of the crude tioconazole based on product of step (a), (i.e., thiophenol converted to brominated intermediate) have been obtained.
Suitable reaction conditions for step (b) comprise a temperature range of about 15xc2x0 C. to about 30xc2x0 C., preferably about 20-25xc2x0 C., most preferably at about room temperature. It was discovered that conducting the reaction at a temperature less than reflux of the solvent results in higher yields, and decreases decomposition of the 2-chloro-2 bromomethylthiophen starting material (which is a severe lacryamator). Additionally, a reaction temperature as close to room temperature as possible minimizes formation of byproducts.
Suitable solvents for the reaction comprise alcohols such as methanol, ethanol, isopropanol, and the like. The reaction is preferably conducted in isopropanol as solvent. Alternate solvents include, but are not limited to short chain alcohols (e.g., C1-6) provided reagents are soluble at room temperature therein. It is preferred to avoid solvents which form peroxides. It was discovered that the coupling product has limited solubility in solvents such as alkanes, aromatics, hexane, heptane, toluene, benzene.
Reaction times for step (b) comprise about 1 to about 24 hours, preferably about 12 hours.
Suitable bases include sodium hydroxide (NaOH), sodium hydride (NaH), potassium hydroxide, sodium isopropoxide and the like. The preferred base to employ is sodium hydroxide.
We have discovered that replacing NaOH for NaH which is normally employed by the art, and using isopropanol as solvent instead of THF eliminates the hazards of a peroxide former, and hence the danger of explosion associated therewith, as well as the evolution of hydrogen gas. When one employs NaH, all reagents go to their respective salts; with NaOH as a base, there is an equilibrium in the reaction. As the reaction proceeds the equilibrium is shifted towards the product and less impurities are formed.
Purify/Conversion to Salt
In accordance with the present invention , the product of step (b) is converted to its corresponding bisulfate salt (not chloride salt as described in the art). To the crude tioconazole formed from step (b) a solvent switch is performed. Water is added to the reaction mixture of step (b) and the isopropanol/cyclohexanol solvent is removed, preferably by distillation. The desired product remains in the pot as an water/oil mixture. Solvent, such as xylene, is added to the water/oil mixture to form 2 mobile phases and the phases are separated. To the organic phase is added sulfuric acid to form the bisulfate salt. Addition of acetone causes formation of white crystals. The white crystals are filtered and recrystallized in an aqueous medium, preferably water. The tioconazole bisulfate salt has a melting point of about 80xc2x0 C.
Relative to the art, the present invention has now eliminated the need for hazardous solvents, use of hydrogen formers, the need to run reactions at elevated or reflux temperatures, and provides a process which allows water as a recrystallization solvent. The tioconazole bisulfate salt has been found to be more readily crystallized than the corresponding chloride salt in water.
To liberate the tioconazole free base, the bisulfate salt is added to a cyclohexane/water mixture and heated. A neutralizing base, preferably ammonium hydroxide is added to the warm solution and phases separated. Base is added in an amount sufficient to neutralize the bisulfate salt. As the cyclohexane solution cools tioconazole crystallizes out of solution. It was truly an accidental discovery to find that the tioconazole is soluble in cyclohexane.
Color Treatment:
As an optional measure, to remove some color bodies formed, aluminum oxide (alumina), alone or in combination with other decolorizing agents is employed. The art generally employs activated carbon to remove color bodies. It was found that alumina in conjunction with activated carbon when added to the liberated tioconazole heated in a suitable solvent, preferably a cycloaliphatic solvent, most preferably cyclohexane, results in a whiter tioconazole product.
For exemplary purposes, the present invention was described in particular detail with respect to the preparation of tioconazole. For preparation of compounds such as econazole or miconazole wherein a similar procedure may be employed, the starting aromatic compounds include dichloro toluene and chloro toluene respectively. Like tioconazole, 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol may be employed as the imidazolyl compound for the coupling step.